Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

• Imidazole and its 1-substituted derivatives inhibit thromboxane synthetase (H.-H. Tai, Biochem. and Biophys. Res. Comm. 80, 236 (1978)).
• TXA 2 The enzyme thromboxane synthetase catalyzes, within arachidonic acid metabolism, the conversion of prostaglandin endoperoxides (PGH 2 and PGG 2 ) into the highly biologically active thromboxane A 2 (TXA 2 ), which induces the aggregation of blood platelets and has a powerful constrictive action on smooth muscle.
• PHL 2 and PGG 2 prostaglandin endoperoxides
• TXA 2 plays an essential part in hemostasis, in pathological situations with an increased tendency to vasospasms and/or thrombosis.
• TXA 2 has a powerful contracting effect on bronchial muscles in vitro and in vivo (B. Samuelson, Angew. Chem., 95, 854 (1983)).
• the new 1-imidazolylalkylnaphthoic acids, their acid derivatives and 1-imidazolylalkylnaphthylmethanols, which are described in the present invention, are distinguished by a specific inhibitory effect on the enzyme thromboxane synthetase.
• the compounds are suitable for the prophylaxis or for the treatment of diseases with a deranged (increased) tendency to platelet aggregation, and where the thromboxane levels are pathologically increased, which are found in association with ischemia, angina pectoris, thromboembolic disorders, atherosclerosis, coronary spasms, arrhythmias, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarct, hypertension, breathing disturbances such as asthma and apnea, inflammatory diseases and microvascular complications associated with diabetes mellitus.
• the compounds according to the invention exert a favorable effect on disorders with increased thromboxane levels in various organs, for example in the region of the kidneys or in the gastrointestinal tract associated with colitis or with inflammatory bowel disease. Moreover, the compounds are suitable for slowing down or for preventing the proliferation of tumor cells.
• European Pat. No. A2-0073663 relates to, inter alia, 1-imidazolylalkylnaphthoic acid derivatives which have pharmacological activity.
• the present invention relates to new 6-(1-imidazolylalkyl)-2-naphthoic acids, to their derivatives and to 6-(1-imidazolylalkyl)-2-naphthylmethanols of the general formula I ##STR2## and to the physiologically tolerated acid addition salts.
• general formula I 6-(1-imidazolylalkyl)-2-naphthoic acids, to their derivatives and to 6-(1-imidazolylalkyl)-2-naphthylmethanols of the general formula I ##STR2## and to the physiologically tolerated acid addition salts.
• R 1 denotes hydrogen, or, in the 2-, 4- or 5-position, a straight-chain or branched alkyl radical having up to 8 carbon atoms, a straight-chain or branched unsaturated hydrocarbon radical having up to 8 carbon atoms and 1-3 double or triple bonds, it being possible for the aliphatic radicals in turn to be substituted 1 to 3 times with halogen, with a carboxyl or carbalkoxy radical having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, cycloalkyl having 3-8 carbon atoms, or with a phenyl, ⁇ -or ⁇ -furyl or ⁇ - or ⁇ -thienyl radical, which in turn can be substituted 1 to 3 times in the nucleis by halogen, trifluoromethyl and/or alkyl or alkoxy having up to 6 carbon atoms, or denotes a straight-chain or branched alkoxy radical having up to 6 carbon atoms, or a pheny
• R 2 denotes hydrogen, a cycloaliphatic hydrocarbon radical having 3-8 carbon atoms, a straight-chain or branched alkyl radical having up to 8 carbon atoms, a straight-chain or branched unsaturated hydrocarbon radical having up to 8 carbon atoms and 1-3 double or triple bonds, it being possible for the aliphatic radicals in turn to be substituted 1-3 times with alkoxy having up to 6 carbon atoms, with cycloalkyl having 3-8 carbon atoms or with a phenyl radical which in turn can be substituted 1-3 times in the nucleus by halogen, trifluoromethyl, alkyl or alkoxy, each having up to 6 carbon atoms, or denotes a carboxyl or carbalkoxy radical having up to 6 carbon atoms, a phenyl radical which in turn can be substituted in the nucleus 1-3 times by halogen, trifluoromethyl, alkyl or alkoxy, each having up to 6 carbon atoms,
• Y denotes a radical of the formula --CO 2 R 3 , ##STR3## or --CH 2 OH, R 3 denoting hydrogen, a straight-chain or branched alkyl radical having up to 8 carbon atoms, a straight-chain or branched unsaturated aliphatic hydrocarbon radical having up to 6 carbon atoms, a cycloaliphatic hydrocarbon radical having 3-7 carbon atoms, an araliphatic hydrocarbon radical having 7-10 carbon atoms, or a physiologically tolerated metal ion, NH 4 ion or an ammonium ion which is derived from a primary, secondary or tertiary amine, or a tetraalkylammonium ion,
• R 4 denoting hydrogen, a straight-chain or branched alkyl radical having up to 8 carbon atoms, a cycloaliphatic hydrocarbon radical having 3-7 carbon atoms, an araliphatic hydrocarbon radical having 7-10 carbon atoms which can be substituted in the nucleus 1-3 times by halogen, trifluoromethyl, alkyl and/or alkoxy, each having 1-6 carbon atoms, or a phenyl radical which can be substituted in the nucleus 1-3 times by halogen, trifluoromethyl, alkyl and/or alkoxy, each having 1-6 carbon atoms,
• R 5 denoting hydrogen, a straight-chain or branched alkyl radical having up to 8 carbon atoms, or a cycloaliphatic hydrocarbon radical having 3-7 carbon atoms, or
• R 6 denoting hydrogen or a straight-chain or branched alkyl radical having 1-6 carbon atoms
• R 1 and R 2 are both hydrogen if Y represents the group CO 2 R 3 , with R 3 representing H or alkyl, or represents the group CONH 2 .
• R 1 Hydrogen, or, in the 5-position, straight-chain or branched alkyl having up to 6 carbon atoms, in particular C 1 -C 4 -alkyl, a straight-chain or branched unsaturated aliphatic hydrocarbon radical having up to 4 carbon atoms, in particular C 2 -C 4 -alkenyl, phenyl-C 1 -C 3 -alkyl, in particular benzyl or 2-phenylethyl, a carboxyalkyl radical having 2 to 4 carbon atoms, in particular carboxymethyl or carboxyethyl, or an alkoxycarbonylalkyl radical having up to 7 carbon atoms, in particular ethoxycarbonylmethyl or methoxycarbonylmethyl or ethoxycarbonylethyl or methoxycarbonylethyl, or phenyl.
• Hydrogen or, in the 5-position, straight-chain or branched alkyl having up to 6 carbon atoms, in particular C 1 -C
• R 2 Hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, in particular C 1 -C 4 -alkyl, a cycloaliphatic hydrocarbon radical having 5-7 carbon atoms, in particular C 5 -C 7 -cycloalkyl, phenyl-C 1 -C 3 -alkyl, in particular benzyl or 2-phenylethyl, phenyl whose nucleus is preferably unsubstituted or is substituted 1-2 times by C 1 -C 3 -alkyl, in particular methyl or ethyl, by C 1 -C 3 -alkoxy, in particular methoxy or ethoxy, by halogen or by trifluoromethyl, or 3-pyridyl which can be substituted in the 4- or 5-position by C 1 -C 4 -alkyl, in particular by methyl or ethyl.
• a cycloaliphatic hydrocarbon radical having 5-7 carbon atoms,
• Y is --CO 2 R 3 , ##STR4## or CH 2 --OH, the following meanings of R 3 , R 4 and R 5 being suitable and preferred:
• R 3 hydrogen, straight-chain or branched alkyl having 1-6 carbon atoms, in particular C 1 -C 4 -alkyl, a straight-chain or branched unsaturated aliphatic hydrocarbon radical having up to 4 carbon atoms, in particular C 2 -C 4 -alkenyl, a cycloaliphatic hydrocarbon radical having 5-7 carbon atoms, in particular C 5 -C 7 -cycloalkyl, phenyl-C 1 -C 3 -alkyl, in particular phenethyl or benzyl, or a physiologically tolerated metal ion, NH 4 ion or an ammonium ion which is derived from a primary, secondary or tertiary amine, in particular:
• Hydrogen methyl, ethyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, 2-propyl, 2-butyl, 2-pentyl, 3-hexyl, 2-methylpropyl, 2-methylbutyl, 4,4-dimethylpentyl, 5,5-dimethylhexyl, cyclopentyl, cyclohexyl, cycloheptyl, methylammonium, dicyclohexylammonium or tris(hydroxymethyl)methylammonium.
• R 4 hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, in particular C 1 -C 4 -alkyl, C 5 -C 7 -cycloalkyl, in particular cyclopentyl and cyclohexyl, phenyl-C 1 -C 3 -alkyl, in particular benzyl and 2-phenylethyl, or a phenyl radical.
• R 5 hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, in particular C 1 -C 4 -alkyl.
• R 1 represents hydrogen or C 1 -C 4 -alkyl or phenyl, each in the 5-position
• R 2 represents hydrogen or C 1 -C 2 -alkyl
• Y represents the COOH or COO--R 3 group, R 3 denoting C 1 -C 4 -alkyl, and the physiologically tolerated acid addition salts.
• the invention also relates to the acid addition salts of the compounds which have been described with inorganic or organic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, oxalic acid, malonic acid, glycollic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid or cinnamic acid.
• inorganic or organic acids for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, oxalic acid, malonic acid, glycollic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid or cinnamic acid.
• the invention also relates to a process for the preparation of compounds of the formula I, which comprises
• Y' denotes the radicals ##STR6## or --COOR 7 , R 7 representing C 1 -C 8 -alkyl, and Hal denotes chlorine or bromine,
• R 8 denotes hydrogen, lower alkanoyl or benzoyl, to give a compound of the formula IV ##STR8## in which R 1 and R 2 have the meanings indicated for formula I, and
• Y' has the meanings indicated for formula II
• Y' represents the radical ##STR9## to give a compound of the formula I, in which Y denotes the radical --COOH,
• Y' has the meanings indicated for formula II.
• 2-Acetylnapthalene derivatives of the general formula V can be prepared by known processes (for example J. Org. Chem., 49, 384 (1984) or Eur. J. Med. Chem.-Chim. Ther., 19, 5 (1984)).
• the imidazolyl ketones of the formula IV can be oxidized in a haloform reaction with chlorine, bromine or iodine, in the presence of a strong base such as, for example, sodium or potassium hydroxide, to give compounds of the formula I, in which Y denotes a carboxyl group.
• reaction products are not obtained in a form which is already sufficiently pure for it to be possible to use them in the subsequent reaction step, purification by crystallization or column, thin-layer or high-pressure liquid chromatography is advisable.
• the compounds of the general formula I exhibit a specific inhibition of thromboxane synthetase and can thus be used as medicaments for the prophylaxis or treatment of diseases with a deranged, i.e. increased, tendency of the platelets to aggregate, as well as when the thromboxane levels are pathologically increased, such as is found in association with ischemia, angina pectoris, thromboembolic disorders, atherosclerosis, coronary spasms, arrhythmias, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarct, hypertension, breathing disturbances such as asthma or apnea, inflammatory disorders and microvascular complications associated with diabetes mellitus.
• the compounds according to the invention exert a favorable effect on disorders with increased thromboxane levels in various organs, for example in the region of the kidneys or the stomach and intestines associated with colitis or inflammatory bowel disease.
• the compounds are, moreover, suitable for slowing down, or even preventing, the proliferation of tumor cells.
• Prostacyclin Prostacyclin
• TXA 2 thromboxane A 2
• Prostacyclin which is formed from prostaglandin endoperoxide H 2 (PGH 2 ) preferentially in the endothelial cells of the blood vessels, brings about vasodilatation and simultaneously prevents the aggregation of platelets.
• the conversion of PGH 2 into prostacyclin is catalyzed by prostacyclin synthetase.
• the physiological antagonist of prostacyclin is thromboxane A 2 , which is synthesized from PGH 2 mainly in the blood platelets. This reaction is catalyzed by the enzyme thromboxane synthetase.
• TXA 2 brings about aggregation of blood platelets and results in vasoconstriction. It is the most potent vasoconstrictor hitherto known in the human body (see A. G. Herman, P. M. Vonhoutte, H. Denolin, A. Goossens, Cardiovascular Pharmacology of the Prostaglandins, Raven Press, New York, 1982). Disturbances of the equilibrium between prostacyclin and thromboxane A 2 result in pathophysiological situations.
• migraine Another area in which a disturbance of the PGI 2 /TXA 2 equilibrium is regarded as being a contributory factor is migraine.
• Migrainous headaches are linked with changes in the intracerebral and extracerebral blood flow, in particular with a reduction in the cerebral blood flow taking place before the manifestation of the headache and with subsequent dilatation in both vascular areas during the headache phase. Platelets from migraine patients have a greater tendency to aggregate than do those from normal individuals (J. clin. Pathol. 24, 250 (1971); J. Headache, 17, 101 (1977); Lancet 1978, 501).
• Non-steroidal antiinflammatory agents inhibit cyclooxygenase, which catalyses the conversion of arachidonic acid into PGH 2 via PGG 2 . Thus they intervene both in the biosynthesis of thromboxane A 2 and in that of prostacyclin. Thus, more valuable compounds would be those which specifically block the formation of thromboxane A 2 by inhibition of thromboxane synthetase and, at the same time, have no effect on the formation of prostacyclin.
• Platelet-rich plasma is obtained in the supernatant by centrifugation at 140 ⁇ g for 15 minutes, and the platelet content of this should be in the range 2.5-3.5 ⁇ 10 8 /ml (Coulter counter).
• the platelet aggregation is followed optically by measurement of the transmission of light in a Born aggregometer.
• the total volume of the test mix is 0.25 ml.
• the preincubation time at 37° C.
• test product 10 min, and aggregation is then induced with 2 ⁇ 10 -4 M arachidonic acid.
• the test product is, as a rule, tested in five different concentrations in the PRP from three different donors. Dose-effect curves are drawn from the maximal aggregation amplitudes in each case, and the IC 50 values* are determined graphically. The measurements are carried out in the period 1-6 hours after blood sampling.
• IC 50 values for the inhibition of the arachidonic acid-induced aggregation of human platelets in vitro were determined by the method described above for the compounds according to the invention:
• Platelet-rich plasma is obtained in the supernatant by centrifugation at 140 ⁇ g for 15 minutes, and the platelet content of this should be in the range 2.5-3.5 ⁇ 10 8 /ml.
• the platelets are sedimented by renewed centrifugation (10 min at 2,000 ⁇ g), and then resolubilized in Tyrode's solution (about 7 ⁇ 10 7 platelets/ml, total volume per measurement 0.5 ml). After addition of test substance, the mixture is incubated at 37° C.
• TXB 2 is determined radioimmunologically (TXA 2 is unstable under the experimental conditions and thus cannot be measured.
• the stable hydrolysis product TXB 2 is measured in its place).
• the investigations of the compounds according to the invention in the model of laser-induced thrombosis are carried out on male or female Sprague-Dawley rats with a body weight of about 200 g.
• the animals to be investigated are premedicated s.c. with 0.1 mg of atropine sulfate in solution, and anesthetized i.p. with 100 mg of ketamine hydrochloride and 4 mg of xylazine per kg of body weight.
• Arterioles from the mesentery, with a diameter of 12-25 ⁇ m, are used for the investigation.
• the exposed mesentery is hyperfused with warmed physiological NaCl (37° C.) or is covered with degassed liquid paraffin.
• the beam of a 4 W argon laser (supplied by Spectra Physics, Darmstadt, FRG) is introduced coaxially into the inverted ray path of a microscope (ICM 405, LD-Epilan 40/0.60; supplied by Zeiss, Oberkochen, FRG) by means of a ray adaptation and adjustment system (supplied by BTG, Kunststoff, FRG).
• the wavelength used is 514.5 nm, with an energy above the objective of 40 mW.
• the single-shot exposure time is 1/15 sec.
• the diameter of the effective laser beam on the vessel is 10 ⁇ m, and with repeated exposure the next shot takes place 5 ⁇ m upstream in each case, directly on the vessel wall.
• test substances were administered orally in various doses in 0.9% sodium chloride solution (contained 1% carboxymethylcellulose, or in appropriate solubilizers) to the experimental animals one hour before the start of the experiment; control animals were treated in a corresponding manner, but without the test substances.
• 0.9% sodium chloride solution obtained 1% carboxymethylcellulose, or in appropriate solubilizers
• the number of shots needed to induce a defined thrombus was counted.
• the frequency of the laser flashes was one lesion every 2 minutes, all the thrombi with a minimum size of 1/4 of the vessel radius which were formed during the observation period being counted and measured.
• the results of the experiment were statistically analyzed using the X 2 test (L. Cavalli-Sforza, Biometrie, Stuttgart, 1969, page 49 et seq.).
• the compounds of the formula I specifically block the formation of thromboxane A 2 by inhibition of thromboxane synthetase, without affecting prostacyclin formation, and are thus suitable for the prevention or for the treatment of the abovementioned disorders which respond to inhibition of thromboxane synthetase.
• the invention thus also relates to the use of the compounds of the formula I, and of their salts, for the treatment of the abovementioned disorders, and to pharmaceutical products based on the compounds according to the invention.
• the compounds of the formula I are administered in various dosage forms, for example orally in the form of tablets, capsules or liquids, rectally in the form of suppositories, parenterally, subcutaneously or intramuscularly, preference being given to intravenous administration in emergency situations.
• the compounds of the formula I can be used as free bases or in the form of their physiologically acceptable inorganic or organic acid addition salts.
• the free bases and acid addition salts can be used in the form of their aqueous solutions or suspensions, or dissolved or suspended in pharmacologically acceptable organic solvents, such as monohydric or polyhydric alcohols such as, for example, ethanol, ethylene glycol or glycerol, in triacetin, in alcohol/acetaldehyde diacetal mixtures, oils such as, for example, sunflower oil or fish liver oil, ethers such as, for example, diethylene glycol dimethyl ether, or polyethers such as, for example, polyethylene glycol, or in the presence of other pharmacologically acceptable polymeric vehicles such as, for example, polyvinylpyrrolidone.
• pharmacologically acceptable organic solvents such as monohydric or polyhydric alcohols such as, for example, ethanol, ethylene glycol or glycerol, in triacetin, in alcohol
• Suitable formulations are the customary pharmaceutical solutions for infusion or injection, and tablets, as well as formulations which can be used locally, such as creams, emulsions, suppositories or aerosols.
• the compounds are active in doses from 0.01 mg/kg to 10 mg/kg.
• the single dose administered can be between 1 mg and 500 mg.
• the preferred daily dose on oral administration is between 1 mg and 1 g.
• the mixture is heated with 44.3 ml (49.6 g, 0.8 mol) of ethylene glycol and 0.5 g of p-toluenesulfonic acid in 800 ml of toluene under reflux with a water separator until no more water separates out and are thus converted into the isomeric ethylene acetals.
• the reaction solution is washed with sodium bicarbonate solution and then evaporated in vacuo. 97.4 g (102%) of a mixture of two isomeric ethylene acetals are obtained, 40 g of which is separated into the isomers by chromatography on silica gel using cyclohexane/ethyl acetate mixtures.

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• 1985
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